Single-Molecule Studies of CFTR Gating and Pharmacology

Author

Jesper Bøegh Levring

Date of Award

2024

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Chen Laboratory

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel expressed in the apical membrane of epithelial tissues. Alterations in CFTR that disrupt activity cause cystic fibrosis, a fatal disease which is characterized by systemic salt and fluid dysregulation. By contrast,hyperactivation of CFTR is central to pathogenesis in secretory diarrhea and autosomal dominant polycystic kidney disease.Electrophysiological properties of CFTR have been analyzed for decades. The structure of CFTR,determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Opening of CFTR’s pore is regulated by phosphorylation- and ATP-dependent dimerization of its two nucleotide-binding domains (NBDs), but how the dimerization process is coupled to pore opening remains contested.Whereas the binding sites for therapeutic potentiators of CFTR gating are known, the mechanism by which they increase channel open probability is not understood.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Levring, Jesper Bøegh, "Single-Molecule Studies of CFTR Gating and Pharmacology" (2024). Student Theses and Dissertations. 764.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/764